Significant advances in therapy for heart failure (HF) with impaired systolic function have improved quality of life, and increased survival. However up to 50% of patients who have clinical evidence of HF are found to have a relatively (or near) normal left ventricular ejection fraction (HF with normal left ventricular (LV) ejection fraction syndrome (HFnEF), also referred to as HF with preserved left ventricular ejection fraction syndrome (HFpEF). Patients with HFnEF represent a rapidly increasing proportion of patients hospitalised and suffering mortality from heart failure.
Despite a normal EF, HFnEF patients manifest subtle systolic dysfunction but the principal abnormality in most is a disorder of active relaxation and/or passive filling of the LV. However resting measures of active relaxation and filling relate poorly to symptoms and exercise capacity therefore no ‘gold standard’ diagnostic echocardiographic test exists for HFnEF. Effective ventricular filling results from a highly energy dependent active relaxation process and from passive filling which is dependent on loading conditions as well as the intrinsic (passive) properties of the LV. Since both these parameters change markedly during exercise due to sympathetic activation, it is not surprising that these resting parameters are so poorly predictive of exercise capacity and symptoms.
The treatment of patients with HFnEF is discussed in Hunt et al., “ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult”, 2005, Section 4.3.2, available at www.acc.org.
Perhexiline (2-(2,2-dicyclohexylethyl)piperidine) is a known anti-anginal agent that operates principally by virtue of its ability to shift metabolism in the heart from free fatty acid metabolism to glucose, which is more energy efficient.
WO-A-2005/087233 discloses the use of perhexiline for the treatment of chronic heart failure (CHF) where the CHF is a result of an initial inciting influence of ischaemia or where the CHF is a result of an initial non-ischaemic inciting influence.